US20100062057A1 - Formulation - Google Patents
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- US20100062057A1 US20100062057A1 US12/207,824 US20782408A US2010062057A1 US 20100062057 A1 US20100062057 A1 US 20100062057A1 US 20782408 A US20782408 A US 20782408A US 2010062057 A1 US2010062057 A1 US 2010062057A1
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- alginate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4816—Wall or shell material
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/56—Materials from animals other than mammals
- A61K35/60—Fish, e.g. seahorses; Fish eggs
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
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- A—HUMAN NECESSITIES
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- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
Definitions
- New seamless capsules comprising at least one oily phase that comprises at least one marine oil and at least one surfactant in an alginate capsule formulation, methods of preparing the same, and uses of thereof are disclosed herein.
- compositions comprising at least one oily phase comprising at least one marine oil encapsulated in an alginate outer surface shell are disclosed.
- the compositions may be seamless capsules with a shell that is thinner compared to the gelatin capsules known in the art, thereby allowing a larger amount of material to be encapsulated.
- the at least one marine oil may thus be administered to a subject for therapeutic treatment and/or regulation of at least one health problem including, for example, irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, hypertriglyceridemia, heart failure, and post myocardial infarction (MI).
- MI myocardial infarction
- cholesterol and triglycerides are part of lipoprotein complexes in the bloodstream and can be separated via ultracentrifugation into high-density lipoprotein (HDL), intermediate-density lipoprotein (IDL), low-density lipoprotein (LDL), and very-low-density lipoprotein (VLDL) fractions.
- HDL high-density lipoprotein
- IDL intermediate-density lipoprotein
- LDL low-density lipoprotein
- VLDL very-low-density lipoprotein
- total-C total-C
- LDL-C LDL-C
- apolipoprotein B a membrane complex for LDL-C and VLDL-C
- apolipoprotein A apolipoprotein A
- cardiovascular morbidity and mortality in humans can vary directly with the level of total-C and LDL-C and inversely with the level of HDL-C.
- non-HDL cholesterol is an important indicator of hypertriglyceridemia, vascular disease, atherosclerotic disease, and related conditions.
- non-HDL cholesterol reduction has been specified as a treatment objective in NCEP ATP III.
- Omega-3 fatty acids may regulate plasma lipid levels, cardiovascular and immune functions, insulin action, and neuronal development, and visual function.
- Marine oils also commonly referred to as fish oils, are a source of omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), that have been found to regulate lipid metabolism.
- Omega-3 fatty acids may have beneficial effects on the risk factors for cardiovascular diseases, for example hypertension and hypertriglyceridemia, and on the coagulation factor VII phospholipid complex activity.
- Omega-3 fatty acids may also lower serum triglycerides, increase serum HDL cholesterol, lower systolic and diastolic blood pressure and/or pulse rate, and may lower the activity of the blood coagulation factor VII-phospholipid complex. Further, omega-3 fatty acids seem to be well tolerated, without giving rise to any severe side effects.
- omega-3 fatty acid is a concentrate of omega-3, long chain, polyunsaturated fatty acids from fish oil containing DHA and EPA and is sold under the trademark LovazaTM, formerly known as Omacor® See, for example, in U.S. Pat. Nos. 5,502,077, 5,656,667 and 5,698,594.
- LovazaTM comprises at least 80% by weight of omega-3-fatty acids, salts or derivatives thereof, wherein (all-Z)-5,8,11,14,17-eicosapentaenoic acid (EPA) and (all-Z)-4,7,10,13,16,19-docosahexaenoic acid comprises at least 75% by weight of the total fatty acids.
- each 900 mg capsule of LovazaTM contains at least 90% omega-3 ethyl ester fatty acids (84% EPA/DHA); approximately 465 mg EPA (eicosapentaenoic acid) ethyl ester and approximately 375 mg DHA (docosahexaenoic acid) ethyl ester.
- Alginate capsules offer several benefits over gelatin capsules known in the art. For example, alginate capsules may be more temperature-stable and humidity-stable than gelatin capsules. Furthermore, alginate capsules do not require testing for bovine spongiform encephalopathy (SSE) as gelatin capsules do, and alginate capsules may decrease gastrointestinal reflux disease symptoms, such as burping. In addition, alginate capsules may be smaller due to a thinner capsule wall. A thinner wall may allow for increased fill volume for the same capsule size. Increased fill volume may result in a greater dosage per capsule, such that a subject would require fewer capsules per day for a given dose. Alginate capsules may be less sticky, such that they would be easier to swallow and not stick together. The capsules may also be clear and colorless in appearance, which may improve the perception to patients.
- SSE bovine spongiform encephalopathy
- FR 2 745 979 discloses alginate capsules comprising omega-3 fatty acids as animal feed additives.
- HU 2 030 38 discloses encapsulation of unsaturated fatty acids, fatty acid esters, and their mixtures using alginated gel.
- enteric capsules containing omega-3 fatty acids For example, U.S. Pat. No. 6,531,150 discloses enteric capsules having a buffer layer of a water-soluble gel containing an acid or acid salt between the content of omega-3 fatty acids and the gelatin-based coating layer. Further, for example, European Patent Application No. EP1529524 and German Application No. DE19930030 disclose gelatin capsules containing omega-3 fatty acids coated with xylose to provide resistance to gastric juice and increase stability. In addition, Belluzi et al., N. Eng. J.
- FIG. 1 shows average plasma concentration versus time curves of EPA and DHA after single oral dose of Omacor® and compositions of the present disclosure comprising K85EE in male minipigs: (a) average EPA plasma concentration after oral dosing of 2 g (2 capsules); (b) average DHA plasma concentration after oral dosing of 2 g (2 capsules); (c) average EPA plasma concentration after oral dosing of 4 g (4 capsules); (d) average DHA plasma concentration after oral dosing of 4 g (4 capsules).
- omega-3 fatty acids includes natural or synthetic omega-3 fatty acids, as well as pharmaceutically acceptable esters, derivatives, conjugates (see, e.g., Zaloga et al., U.S. Patent Application Publication No. 2004/0254357, and Horrobin et al., U.S. Pat. No. 6,245,811, each hereby incorporated by reference), precursors, salts, and mixtures thereof.
- omega-3 fatty acid oils include, but are not limited to, omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ⁇ -linolenic acid; esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides; and esters of the omega-3 fatty acids and a primary, secondary and/or tertiary alcohol, such as, for example. fatty acid methyl esters and fatty acid ethyl esters.
- omega-3 polyunsaturated, long-chain fatty acids such as a eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and ⁇ -linolenic acid
- esters of omega-3 fatty acids with glycerol such as mono-, di- and triglycerides
- Preferred omega-3 fatty acid oils are long-chain fatty acids, for example, EPA and DHA, triglycerides thereof, ethyl esters thereof, and/or mixtures thereof.
- the omega-3 fatty acids, their esters, derivatives, conjugates, precursors, salts and/or mixtures thereof can be used in their pure form and/or as a component of an oil, for example, as marine oil, for example fish oil, such as purified fish oil concentrates.
- omega-3 fatty acids s include Incromega F2250, F2628, E2251, F2573, TG2162, TG2779, TG2928, TG3525 and E5015 (Croda International PLC, Oxford, England), and EPAX6000FA, EPAX5000TG, EPAX4510TG, EPAX2050TG, K85TG, K85EE, K80EE, and EPAX7010EE.
- omega-3 fatty acids are chosen from LovazaTM (formerly Omacor®/), K85, and AGP-103.
- omega-3 fatty acids are esterified, such as alkyl esters. Those alkyl esters include, but are not limited to ethyl, methyl, propyl, and butyl esters, and mixtures thereof.
- the omega-3 fatty acids are present in the form of free fatty acids.
- the omega-3 fatty acids may chosen from mono-, di-, and triglycerides. In another embodiment, the omega-3 fatty acids are in the form of a phospholipid.
- the omega-3 fatty acids according to the present disclosure may derive from animal oils, such as marine oil, such as fish oil, krill oil, or lipid composition derived from fish.
- the oil is a an active pharmaceutical ingredient (API).
- the oil is a nutritional supplement.
- the oil is a flavor oil, a food, and/or a food additive.
- Said oil may also be a carrier for oil-soluble active materials, wherein said oil-soluble active material comprises another pharmaceutical agent, nutritional agent, flavor, fragrance, or a food.
- alginate includes alginic acid and/or pharmaceutically acceptable salts thereof, and refers generally to a copolymer comprising (1-4)-linked ⁇ -D-mannuronate (M) and its C-5 epimer ⁇ -L-guluronate (G) residues.
- alginate salts suitable for the disclosure herein include alginate salts of calcium, strontium, barium, or aluminum.
- alginate comprises all or in part M-alginate.
- alginate comprises all or in part G-alginate.
- alginate comprises a combination of M-alginate and G-alginate.
- the alginate has a G content of at least 30% by weight. In other embodiments, the alginate has a content ranging from about 40% to about 80% by weight.
- the alginate shell achieves a time-release delivery of omega-3 fatty acids upon administration to a subject.
- the alginate shell further comprises coloring agents, stabilizers, sweetening agents, plasticizers, and/or hardeners.
- polymers contemplated as comprising the capsule shell include polyesters, polyacrylates, polycyanoacrylates, polysaccharides, polyethylene glycol, and mixtures thereof.
- Other polymers may include, for example, gelatin, carboxymethylcellulose alginates, carrageenans, pectins, ethyl cellulose hydroxypropyl methylcellulose, cellulose acetophthalate, hydroxypropyl methylcellulose phthalate, methylacrylicacid copolymers (Eudragit® Land S), dimethylaminoethylmethacrylate copolymers (Eudragit E), trimethylammoniumethylmethacrylate copolymers (e.g., Eudragit® RL and RS), polymers and copolymers of lactic and glycolic acids, and mixtures thereof.
- the polymer comprises a plasticizer additive, such as, for example, but not limited to, triethyl citrate, butyl phthalate, and mixtures thereof.
- a plasticizer additive such as, for example, but not limited to, triethyl citrate, butyl phthalate, and mixtures thereof.
- Other additives may optionally be incorporated to improve and/or facilitate the encapsulation process, such as, for example, fluidizing agents, such as talc.
- the seamless capsules of the present disclosure may comprise at least one non-active pharmaceutical ingredient (also known generally herein as “excipients”).
- Non-active ingredients may solubilize, suspend, thicken, dilute, emulsify, stabilize, preserve, protect, color, flavor, and/or fashion active ingredients into an applicable and efficacious preparation, such that it may be safe, convenient, and/or otherwise acceptable for use.
- the at least one non-active ingredient may include be chosen from colloidal silicon dioxide, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, and xanthum gum.
- Surfactants may be chosen from, for example, glycerol acetates and acetylated glycerol fatty acid esters, such as acetin, diacetin, triacetin, and/or mixtures thereof.
- Suitable acetylated glycerol fatty acid esters include, but are not limited to, acetylated monoglycerides, acetylated diglycerides, and/or mixtures thereof.
- the surfactant may be chosen from glycerol fatty acid esters, such as, for example, those comprising a fatty acid component of about 6-22 carbon atoms.
- Glycerol fatty acid esters can chosen from monoglycerides, diglycerides, triglycerides, and/or mixtures thereof. Suitable glycerol fatty acid esters include monoglycerides, diglycerides, medium chain triglycerides with fatty acids having about 6-12 carbons, and/or mixtures thereof.
- Capmul® MCM medium chain mono- and di-glycerides is an example.
- the at least one surfactant may be chosen from propylene glycol esters.
- propylene glycol esters include, but are not limited to, propylene carbonate, propylene glycol monoacetate, propylene glycol diacetate, propylene glycol fatty acid esters, acetylated propylene glycol fatty acid esters, propylene glycol fatty acid monoesters, propylene glycol fatty acid diesters, and mixtures thereof.
- Fatty acids may comprise, for example, about 6-22 carbon atoms.
- propylene glycol esters include, but are not limited to, propylene glycol monocaprylate (Capryol®), propylene glycol dicaprylate, propylene glycol dicaprate, propylene glycol dicaprylate/dicaprate, and mixtures thereof.
- the at least one surfactant may be chosen from ethylene glycol esters, such as, for example, monoethylene glycol monoacetates, diethylene glycol esters, polyethylene glycol esters, and mixtures thereof. Additional examples include ethylene glycol monoacetates, ethylene glycol diacetates, ethylene glycol fatty acid monoesters, ethylene glycol fatty acid diesters, and mixtures thereof.
- the ethylene glycol esters may be chosen from polyethylene glycol fatty acid monoesters, polyethylene glycol fatty acid diesters, and mixtures thereof.
- Ethylene glycol esters may be obtained from the transesterification of polyethylene glycol and a triglyceride, a vegetable oil, and/or mixture thereof, and include, for example, those marketed as Labrafil® and Labrasol®.
- Polyoxyethylene-sorbitan-fatty acid esters also called polysorbates, e.g., of from 4 to 25 alkylene moieties, for example monolauryl, trilauryl, palmityl, stearyl, and oleyl esters, including, for example, Tween®.
- a group of suitable surfactants includes propylene glycol monocaprylate, mixtures of glycerol and polyethylene glycol esters of long fatty acids, polyethoxylated castor oils, nonylphenol ethoxylates (Tergitol®), glycerol esters, oleoyl macrogol glycerides, propylene glycol monolaurate, propylene glycol dicaprylate/dicaprate, polyethylene-polypropylene glycol copolymer, and polyoxyethylene sorbitan monooleate.
- Hydrophilic solvents which may be used include, but are not limited to, alcohols, e.g., a water miscible alcohol such as absolute ethanol, and/or glycerol.
- Alcohols include glycols, e.g., any glycol obtainable from an oxide such as ethylene oxide, e.g., 1,2-propylene glycol.
- glycols e.g., any glycol obtainable from an oxide such as ethylene oxide, e.g., 1,2-propylene glycol.
- polyols e.g., a polyalkylene glycol, e.g., poly(C 2-3 )alkylene glycol.
- One non-limiting example is a polyethylene glycol.
- the hydrophilic component may comprise an N-alkylpyrollidone, such as, but not; limited to, N—(C 1-14 alkyl)pyrollidone, e.g., N-methylpyrollidone,tri(C 1 - 4 alkyl)citrate, e.g., triethylcitrate, dimethylisosorbide, (Cscl 3) alkanoic acid, e.g., caprylic acid and/or propylene carbonate.
- N—(C 1-14 alkyl)pyrollidone e.g., N-methylpyrollidone,tri(C 1 - 4 alkyl)citrate, e.g., triethylcitrate, dimethylisosorbide, (Cscl 3) alkanoic acid, e.g., caprylic acid and/or propylene carbonate.
- N—(C 1-14 alkyl)pyrollidone e.g., N-methylpyrollidone,
- the hydrophilic solvent may comprise a main or sole component, e.g., an alcohol, e.g., C 1-4 -alcohol, e.g., ethanol, or alternatively a component, e.g., which may be chosen from partial lower ethers or lower alkanols.
- Suitable partial ethers include, for example, Transcutol® (which has the formula C2Hs-[O—(CH2)2]2-0H), Glycofurol® (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether), or lower alkanols such as ethanol, such as, for example, glycerol acetates and acetylated glycerol fatty acid esters.
- the capsules are seamless and comprise a polysaccharide gel membrane outer surface shell, and optionally a coating on said gel membrane.
- the polysaccharide gel membrane may be ionic.
- the seamless capsules encapsulate an oily phase comprising at least one marine oil, water, and at least one surfactant.
- the oily phase is an emulsion, such as an oil-in-water emulsion, a water-in-oil emulsion, or a water-in-oil-in-water emulsion.
- the marine oil is present in an amount of at least 50% by weight of the emulsion, such as at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, or even at least 90% by weight of said emulsion.
- the seamless capsules do not comprise marmelo mucilage.
- the polysaccharide gel membrane further comprises one or more secondary film formers chosen from cellulose acetate phthalate, cellulose acetate succinate, methyl cellulose phthalate, ethylhydroxycellulose phthalate, polyvinylacetatephtalate, polyvinylbutyrate acetate, vinyl acetate-maleic anhydride copolymer, styrene-maleic mono-ester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer, propylene glycol alginate, polyvinyl alcohol, carrageenans, pectins, chitosans, guar gum, gum acacia, sodium carboxymethylcellulose, hydroxypropylmethyl cellulose, hydroxypropylcellulose, methylcellulose, starches, and maltodextrins.
- secondary film formers chosen from cellulose acetate phthalate, cellulose acetate succinate
- the polysaccharide gel membrane comprising the seamless capsules is an ionic gel membrane comprising at least one of alginate, propylene glycol alginate, and pectin.
- Said at least one of alginate, propylene glycol alginate, and pectin may be present in the form of a pharmaceutically-acceptable salt, non-limiting examples of which include salts of calcium, strontium, barium, or aluminum.
- the ionic polysaccharide of the seamless capsules presently disclosed may comprise an alginate having a weight-average molecular weight ranging from about 20,000 Daltons to about 500,000 Daltons, such as from about 50,000 Daltons to about 500,000 Daltons, or about 100,000 Daltons to about 500,000 Daltons, or about 150,000 Daltons to about 500,000 Daltons, or about 150,000 Daltons to about 300,000 Daltons, or about 20,000 Daltons to about 200,000 Daltons, or from about 20,000 Daltons to about 100,000 Daltons, or from about 30,000 Daltons to about 80,000 Daltons, or from about 30,000 Daltons to about 60,000 Daltons, or even ranging from about 30,000 Daltons to about 40,000 Daltons.
- the ionic polysaccharide comprises a mixture of two alginate components, such as a mixture of (i) an alginate having a weight-average molecular weight ranging from about 30,000 Daltons to about 40,000 Daltons; and (ii) an alginate having a weight-average molecular weight ranging from about 150,000 Daltons to about 500,000 Daltons.
- the ratio of (i) to (ii), (i):(ii) may range from about 0.1 to about 20, or about 1 to about 16.
- the seamless capsules presently disclosed may be in a shape other than spherical.
- the seamless capsules are oblong, oval, or cylindrical.
- the seamless capsules may be wet or dry.
- the thickness of the polysaccharide gel film comprising the alginate shell of the seamless capsules presently disclosed may range from about 0.01 millimeter to about 50 millimeters.
- the polysaccharide gel film may be wet or dry. In some embodiments, the thickness of the polysaccharide gel film ranges from about 0.3 millimeters to about 4 millimeters. In some embodiments, the thickness of the polysaccharide gel film ranges from about 0.04 millimeters to about 0.5 millimeters.
- the seamless capsules according to the present disclosure may have a wet capsule diameter ranging from about 0.5 millimeters to about 50 millimeters, such as about 1 millimeter to about 40 millimeters, wherein the gel membrane has a thickness ranging from about 0.1 millimeter to about 5 millimeters, such as about 0.3 millimeters to about 4 millimeters.
- the seamless capsule is dried, and the gel membrane is a dry polysaccharide gel film on the outer surface which constitutes up to 10% by weight of the dried seamless capsule.
- the dry capsule has a diameter ranging from about 0.5 millimeters to about 35 millimeters, wherein the dry polysaccharide gel film has a thickness ranging from about 0.01 millimeters to about 5 millimeters. In some embodiments, the thickness of the dry polysaccharide gel film ranges from about 0.04 millimeters to about 0.5 millimeters.
- the omega-3 fatty acids may be administered to a subject in seamless capsules in a daily amount ranging from about 0.100 g to about 10.000 g, such as about 0.500 g to about 8.000 g, including from about 0.250 g to about 5.000 g and about 0.400 g to about 2.000 g.
- the seamless capsules comprising omega-3 fatty acids may be present, for example, in an amount ranging from about 0.100 g to about 4.000 g, such as about 1.000 g to about 4.000 g, further such as 2.000 g and/or 4.000 g unit dosages.
- the seamless capsules are administered to a subject in a unit dose ranging from about 0.400 g to about 2.000 g, such as about 0.400 g to about 1.740 g, such as about 0.420 g to about 1.680 g.
- the daily dosage of omega-3 fatty acids can be administered in from 1 to 10 dosages, such as from 1 to 4 times a day.
- the administration may be oral or any other form of administration that provides a dosage of omega-3 fatty acid to a subject.
- the formulation(s) of the present invention may allow for improved effectiveness of active ingredients, with one or both administered as a conventional full-strength dose, as compared to the formulations in the prior art.
- the formulation(s) of the present invention may allow for reduced dosages of omega-3 fatty acids as compared to the formulations in the prior art, while still maintaining or even improving upon the effectiveness of each active ingredient.
- an oil-in-water emulsion is encapsulated in seamless capsules for oral administration.
- the seamless capsules may also be known generally as softgels.
- Seamless capsules of the present disclosure may be prepared, for example, by a method disclosed in WO 2003/084516, comprising: (a) preparing an emulsion comprising oil, water, an emulsifier, and at least one of a water-soluble monovalent metal salt, polyvalent metal salt, and an acid, wherein the oil is present in an amount of at least 50% by weight of the emulsion; and (b) adding at least one portion of the emulsion to an aqueous gelling bath comprised of at least one ionic polysaccharide, thereby encapsulating the at least one portion of the emulsion in a polysaccharide gel membrane, and optionally (c) drying the resulting capsules.
- the at least one polyvalent metal salt is calcium chloride (CaCl 2 ) and the at least one ionic polysaccharide is alginate.
- the alginate is all or in part M-alginate.
- the alginate is all or in part G-alginate.
- the alginate is a mixture of M-alginate and G-alginate.
- An advantage of having an omega 3 fatty acid oil and encapsulated dihydropyridine calcium blockers together in an alginate capsule, compared to a gelatin capsule, may be the opportunity to include an increased volume of the omega 3 fatty acids as active ingredients because the average film thickness of the seamless alginate capsule is significantly thinner, such as about 20% thinner, or 25% thinner, or even 30% thinner, than a gelatin film.
- alginate capsules may have an increased fill volume which allows for a larger dosage per unit volume of the capsule.
- the fill volume of the capsule may increase by about 20%, or about 25%, or even about 30%, in comparison to gelatin capsules.
- a fewer number of alginate capsules may be administered to a subject in order to achieve the same treatment, such as administration of 3 alginate capsules in place of 4 gelatin capsules.
- a smaller capsule can also be produced that has the same dosage as a larger gelatin capsule.
- the smaller size may increase patient compliance in that the capsules are more easily swallowed.
- the larger dosage per unit volume of capsule may decrease the number of capsules that would need to be taken to reach a given dose of the active pharmaceutical ingredient (API).
- API active pharmaceutical ingredient
- API generally includes marine oil, such as fish oil, krill oil, and lipid compositions derived from fish, as well as omega-3 fatty acids comprising the marine oil.
- the seamless capsules presently disclosed may comprise other active pharmaceutical ingredients in addition to marine oil.
- the seamless capsules presently disclosed may be particularly suitable for large dose actives, acid-sensitive actives, or actives generating gastric irritation, or oxygen-sensitive actives.
- a single seamless alginate capsule of the present disclosure may thus comprise less or more API than the amount of a gelatin capsule of the same size.
- the seamless capsules presently disclosed may comprise about 0.5, 1, 1.5, or even 2 times the amount of API as compared to a gelatin capsule of the same size.
- a single seamless capsule comprises about 0.400 g to about 0.440 g of active pharmaceutical ingredient.
- a single seamless capsule comprises about 0.800 g to about 0.880 g of active pharmaceutical ingredient.
- a single seamless capsule comprises about 1.200 g to about 1.400 g of active pharmaceutical ingredient.
- a single seamless capsule comprises about 1.680 g of active pharmaceutical ingredient.
- a single seamless capsule comprises about 1.740 g of active pharmaceutical ingredient.
- microcapsules may be carried out following any of the methods described in the literature. By way of description and without being limited thereto, the different processes of obtaining microcapsules could be grouped into the following categories:
- a solution of the polymer and possible additives of the polymer in a suitable solvent is prepared.
- the drug to be encapsulated is suspended in said solution and a non-solvent of the polymer is added so as to force the deposit of the polymer on the drug crystals.
- a non-solvent of the polymer is added so as to force the deposit of the polymer on the drug crystals. Examples of such processes can be found in, for example, ES 2009346, EP 0 052 510, and EP 0346879.
- Complex coacervation method is based on the interaction between two colloids that have opposite electric charges, which generates an insoluble complex that is deposited on the particles of the drug to be encapsulated, forming a membrane that will isolate the drug. Examples of such processes can be found, for example, in GB 1393805.
- the drug to be encapsulated is dissolved in water or in a solution of some other coadjuvant and is emulsified in a solution of polymer and additives in a suitable solvent, such as for example dichloromethane.
- a suitable solvent such as for example dichloromethane.
- the resulting emulsion is in turn emulsified in water or in an aqueous solution of an emulsifying agent, such as polyvinyl alcohol.
- an emulsifying agent such as polyvinyl alcohol.
- the drug to be encapsulated, the polymer, and the additives are dissolved together in a suitable solvent.
- This solution is emulsified in water or in an emulsifier solution, such as polyvinyl alcohol, and the organic solvent is eliminated by evaporation or by extraction.
- the resulting microcapsules are recovered by filtration or drying. Examples of these processes can also be found, for example, in U.S. Pat. No. 5,445,832.
- the drug to be encapsulated, the polymer, and additives are dissolved together in a suitable solvent. This solution is evaporated and the resulting residue is micronized to the suitable size. Examples of this process can also be found, for example, in GB 2,209,937.
- the above methods may provide for continuous processing and flexibility of batch size.
- the capsules presently disclosed may be manufactured in low oxygen conditions to inhibit oxidation of the omega-3 fatty acids and/or additional active pharmaceutical ingredients during the manufacturing process.
- the seamless capsules according to the present disclosure comprising omega-3 fatty acids may be administered to a subject for therapeutic treatment.
- the capsules may be administered to a subject to regulate at least one health problem, for example, irregular plasma lipid levels, cardiovascular functions, immune functions, visual functions, insulin action, neuronal development, hypertriglyceridemia, heart failure, and post myocardial infarction.
- An oil-in-water emulsion was prepared by combining:
- the emulsion was extruded through a nozzle and cut into fragments, which were then dropped into a gelling bath.
- the gelling bath comprised 10-80% calcium alginate.
- the resulting capsules were washed in purified water and held in an aqueous plasticizer solution comprising 10-80% pharmaceutical grade glycerine. The capsules were then dried.
- Bioaccessibility potential availability for intestinal absorption
- n-3 fatty acids EPA and DHA
- M-alginate and G-alginate two alginate compositions
- Omacor a gelatin formulation
- Experiments were performed under simulated fasting state conditions during transit through a dynamic gastrointestinal model of the stomach and small intestine. During the experiments, samples from different sites of the GI tract were taken in time to provide good insight on the (rate of) digestibility and kinetics of absorption of the nutrients or the stability and activity of functional ingredients.
- Omacor® (composition 1) was commercially-available, and compositions (2) and (3) were prepared according to Example 1. The study was performed in a dynamic, multi-compartmental system of the stomach and small intestine simulating the successive dynamic conditions in the gastric-small-intestinal tract, such as body temperature, the pH curves, concentrations of electrolytes, and the activity of enzymes in the stomach and small intestine, the concentrations of bile salts in the different parts of the gut (for the production of micelles), and the kinetics of transit of the GI contents through the stomach and small intestine.
- the stomach and small intestine simulating the successive dynamic conditions in the gastric-small-intestinal tract, such as body temperature, the pH curves, concentrations of electrolytes, and the activity of enzymes in the stomach and small intestine, the concentrations of bile salts in the different parts of the gut (for the production of micelles), and the kinetics of transit of the GI contents through the stomach and small intestine.
- a specific filtration system was used to remove products of lipid digestion and lipophilic compounds that are incorporated in micelles. The removed material was collected to determine the bio-accessible fraction of fatty acids, cholesterol and fat soluble nutrients/compounds.
- the M-alginate capsules did not open at the same time in the simulations as in a phosphate buffer.
- EPA and DHA did not release and become bioaccessible during passage through the upper GI tract under fast or fed-state conditions.
- Phosphate was likely involved in dissociation of the alginate capsules; simulated electrolyte solutions did not contain phosphate.
- phosphate mainly derives from the meal, with small amounts coming from the pancreas and bile secretion.
- Bioavailability of the compositions presently disclosed was studied in an animal (minipig; 5-6 months old) model representative of the human digestive system.
- First all animals received 2 g of Omacor, followed in the next week by 2 g of K85EE alginate capsules (composition 2 as described in Example 1). This was subsequently repeated for the high dose groups (4 g) in the third and fourth week. Blood collection took place at pre-dose, 1, 2, 4, 6, 8, 10, 12, 16, 24, and 36 weeks after dosing.
- EPA and DHA concentrations were determined as well as cholesterol, triglycerides and HDL levels.
- An additional set of parameters were determined at pre-dose and 24 h after dosing in the high dose groups; i.e., platelet count (Plt), alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), bilirubin (Tbil), prothrombine time (PTT), fibrogen (Fib), and activated partial thromboplastine time (APTT).
- the K85EE alginate capsules showed a higher uptake of EPA and DHA in comparison with Omacor.
- the C max of the K85EE alginate capsules was 27.7 mg/L and for Omacor 22.3 mg/L.
- the T max was later for the K85EE alginate capsules than for Omacor, i.e., 21 hours versus 9.5 h, respectively.
- the C max of the K85EE alginate capsules was 18.6 mg/L and for Omacor 14.1 mg/L.
- the T max between both formulations was similar (6.5 h).
- the AUC0-n for K85EE alginate was on average found to be 1.6 times higher for EPA in comparison with Omacor and 1.9 times higher for DHA.
- the high dose group also showed a higher uptake with the K85EE alginate capsules of EPA and DHA in comparison with Omacor.
- EPA a C max of the K85EE alginate capsules was 71.7 mg/L and for Omacor 25.53 mg/L.
- the T max was earlier for the K85EE alginate capsules than for Omacor, i.e., 11.5 hours versus 23 h respectively.
- DHA the C max of the K85EE alginate capsules was 42.4 mg/L and for Omacor 17.5 mg/L.
- the T max for the K85EE alginate capsules was 4.5 h versus 17.5 h for Omacor.
- the AUC 0-tn for K85EE alginate was on average found to be 1.5 times higher for EPA in comparison with Omacor and 1.7 times higher for DHA. Results appear in FIGS. 1 a - d.
- the K85EE alginate capsules presented a higher bioavailability than Omacor in both dose groups.
- the bioavailability of EPA was around 1.6 times higher and, for DHA, 1.9 times higher in comparison with Omacor.
- the relative bioavailability of K85EE Alginate capsules was even higher, i.e., 2.5 times for both EPA and DHA in comparison with Omacor.
- an oral dose of 4 g the bioavailability of EPA was 1.5 times higher and for DHA 1.7 times higher in comparison with Omacor.
- the present data support an enhanced bioavailability of EPA and DHA from the K85EE alginate capsules as compared to Omacor.
- Seamless capsules are prepared according to the procedure of Example 1 for administration to a subject.
- the capsules are prepared in different unit dosages:
- the active pharmaceutical ingredient is EPA DHA present in ester or in acid form, wherein each single seamless capsule comprises about 0.400 g to about 0.440 g API. Thus, each capsule comprises about 0.5 times the amount of API of a comparative gelatin capsule.
- the active pharmaceutical ingredient is EPA DHA present in ester or in acid form, wherein each single seamless capsules comprises about 0.800 g to about 0.880 g API.
- each capsule comprises about the same amount (about 1 time the amount) of API of a comparative gelatin capsule.
- the active pharmaceutical ingredient is EPA DHA present in ester or in acid form, wherein each single seamless capsules comprises about 1.200 g to about 1.400 g API. Thus each capsule comprises about 1.5 times the amount of API of a comparative gelatin capsule.
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AU2009290542A AU2009290542A1 (en) | 2008-09-10 | 2009-09-10 | A polysaccharide capsule enclosing a fatty acid oil-containing emulsion |
US13/062,997 US20110262534A1 (en) | 2008-09-10 | 2009-09-10 | polysaccharide capsule enclosing a fatty acid oil-containing emulsion |
CA2736812A CA2736812A1 (en) | 2008-09-10 | 2009-09-10 | A polysaccharide capsule enclosing a fatty acid oil-containing emulsion |
KR1020117008242A KR20110058881A (ko) | 2008-09-10 | 2009-09-10 | 지방산 오일-함유 에멀션을 포함한 폴리사카라이드 캡슐 |
BRPI0918429A BRPI0918429A2 (pt) | 2008-09-10 | 2009-09-10 | cápsulas, emulsões de óleo em água e métodos de regulação de pelo menos um problema de saúde |
PCT/IB2009/006933 WO2010029433A1 (en) | 2008-09-10 | 2009-09-10 | A polysaccharide capsule enclosing a fatty acid oil-containing emulsion |
CN2009801446021A CN102209534A (zh) | 2008-09-10 | 2009-09-10 | 包封含脂肪酸油乳剂的多糖胶囊 |
JP2011526590A JP2012502090A (ja) | 2008-09-10 | 2009-09-10 | 脂肪酸油含有乳剤を封入した多糖類カプセル |
MX2011002640A MX2011002640A (es) | 2008-09-10 | 2009-09-10 | Capsula de polisacarido que comprende una emulsion que contiene aceite de acido graso. |
EA201170433A EA201170433A1 (ru) | 2008-09-10 | 2009-09-10 | Полисахаридная капсула, включающая в себя эмульсию, содержащую масло жирных кислот |
EP09812757.4A EP2341901A4 (en) | 2008-09-10 | 2009-09-10 | POLYSACCHARIDE CAPSULE COMPRISING A CONTENT EMULSION OF FATTY ACID OIL |
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EP (1) | EP2341901A4 (es) |
JP (1) | JP2012502090A (es) |
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CN (1) | CN102209534A (es) |
AU (1) | AU2009290542A1 (es) |
BR (1) | BRPI0918429A2 (es) |
CA (1) | CA2736812A1 (es) |
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2008
- 2008-09-10 US US12/207,824 patent/US20100062057A1/en not_active Abandoned
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- 2009-09-10 EA EA201170433A patent/EA201170433A1/ru unknown
- 2009-09-10 AU AU2009290542A patent/AU2009290542A1/en not_active Abandoned
- 2009-09-10 JP JP2011526590A patent/JP2012502090A/ja active Pending
- 2009-09-10 BR BRPI0918429A patent/BRPI0918429A2/pt not_active IP Right Cessation
- 2009-09-10 CA CA2736812A patent/CA2736812A1/en not_active Abandoned
- 2009-09-10 WO PCT/IB2009/006933 patent/WO2010029433A1/en active Application Filing
- 2009-09-10 US US13/062,997 patent/US20110262534A1/en not_active Abandoned
- 2009-09-10 EP EP09812757.4A patent/EP2341901A4/en not_active Withdrawn
- 2009-09-10 CN CN2009801446021A patent/CN102209534A/zh active Pending
- 2009-09-10 KR KR1020117008242A patent/KR20110058881A/ko not_active Application Discontinuation
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Also Published As
Publication number | Publication date |
---|---|
BRPI0918429A2 (pt) | 2015-11-24 |
AU2009290542A1 (en) | 2010-03-18 |
CA2736812A1 (en) | 2010-03-18 |
EP2341901A4 (en) | 2013-07-17 |
WO2010029433A1 (en) | 2010-03-18 |
CN102209534A (zh) | 2011-10-05 |
EP2341901A1 (en) | 2011-07-13 |
AU2009290542A2 (en) | 2011-03-31 |
JP2012502090A (ja) | 2012-01-26 |
MX2011002640A (es) | 2011-04-07 |
KR20110058881A (ko) | 2011-06-01 |
EA201170433A1 (ru) | 2011-10-31 |
US20110262534A1 (en) | 2011-10-27 |
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